Sickle cell disease (SCD) afflicts millions of people worldwide with chronic and acute pain. Intense pain can start during infancy and increase in severity throughout life in SCD. Patients often require recurrent hospitalization, long-term use of high-dose opioids and live a poor quality of life. Chronic opioid use is associated with side-effects including overdose and death. There is an unmet need to develop non-toxic, non-addictive, non-pharmacologic therapies to treat pain in SCD. We propose to develop a novel transcranial focused ultrasound (tFUS) technology with improved spatial targeting capability for pain treatment, and further integrating with non-invasive electrophysiological source imaging (ESI) for functionally tracking the ultrasound target. We propose to develop, and test a novel noninvasive ESI-guided closed-loop tFUS device, for safely and effectively treating pain in SCD. We will use an existing animal model for SCD pain indication to be addressed by the proposed tFUS device. Our proposed work involves developing novel tFUS device for pain treatment and establishing its effectiveness for treating SCD pain in humanized mice, and safety evaluation and design-oriented scaling up in larger animals. The specific aims are: Aim 1: Developing tFUS neuromodulation device for pain management. We will develop an operational tFUS device for pain treatment, identifying practical transducer characteristics of the random array transducer that can achieve better than 2 mm lateral resolution and better than 3 mm axial resolution for tFUS targeting. Aim 2: Evaluating tFUS effectiveness and optimizing stimulation parameters in SCD mice model. We will obtain the knowledge of effective tFUS parameters in reducing the SCD pain and will achieve at-least 1 hour long lasting treatment effect. Aim 3: ESI-informed closed-loop tFUS in animal models and its safety evaluation. The tFUS system will be fully developed and evaluated for pain management with ESI beam tracking capability with spatial accuracy better than 5 mm. Specifications of the tFUS system will be finalized, including the input and output parameters. The successful completion of the proposed project promises to develop a transformative, noninvasive transcranial focused ultrasound device for effectively and safely treating pain in sickle cell disease. Such non-pharmacologic analgesic therapy would be highly beneficial for SCD patients because of the often life-long pain.